Cardio-pulmonary diseases are the leading cause of morbidity and mortality worldwide. Despite recent advances in drug therapy and improvements in patient care, cardio-pulmonary diseases remains a fatal disease. Angiotensin converting enzyme 2 (ACE2) and angiotensin-1-7[Ang-(1-7)], protective axis of the renin angiotensin system (RAS), has emerged as highly effective in producing beneficial effects on metabolic, immune and cardio- pulmonary dysfunctions by blocking apoptosis, fibrosis, oxidative stress, and inflammation. Recent findings from our team and others provide unequivocal support that the ACE2/Ang-(1-7) axis plays a protective role against cardio-pulmonary diseases. However, the biggest impediment to translate this fundamental knowledge into clinical applications for management and treatment of these diseases is large-scale production of high quality ACE2 and Ang-(1-7) with sufficient target tissue bioavailability. Medosome Biotec, LLC and its research partners at the University of Florida have identified a solution that offers tremendous commercial potential for treating cardio-pulmonary diseases. The team hypothesizes that recombinant probiotics-based oral delivery of protein therapeutics represent an innovative, more efficient and cost-effective strategy to enhance this protective axis at both circulating and target tissues for clinical application. Preliminary data from our UF team members have demonstrated that (1) ACE2 and Ang-(1-7) can be efficiently expressed and secreted from the probiotic bacterium, Lactobacillus paracasei , and reach therapeutic levels in the circulation and target tissues using plasmid vectors that contain antibiotics resistant gene as selection marker; (2) oral administration of Lactobacillus paracasei expressing Ang-(1-7) prevented monocrotaline (MCT)-induced pulmonary hypertension, gut pathophysiology and dysbiosis. The overall objective of this project is to construct and characterize antibiotics- marker free vectors for expression of ACE2 and Ang-(1-7) in probiotics, and confirm their efficacy in animal models of pulmonary hypertension. The completion of these studies will position us to initiate Phase II studies in which we will conduct preclinical experiments that will enable us to submit a completed IND application to the FDA Center for Biologics. In addition, we will build capacity for producing GMP grade material for the clinical trials.